The present study was designed to determine the effectiveness, tolerability, and safety of different doses of oral type II collagen (Colloral) therapy in patients with RA. 274 patients with RA were entered from 6 sites and randomized to receive placebo or one of four doses (20, 100, 500, and 2500 5g/d) of oral Colloral for 24 weeks. Efficacy parameters were assessed at baseline and monthly during the trial and included swollen and tender joint counts, patient and physician global assessments of disease severity, grip strength, 50 foot walk time, during of morning stiffness, functional capacity, and serum levels of acute phase reactants. 83% of the patients completed the 24 week trial. Trends were observed for improvement in all of the disease measures for patients in the 20 5g dosage group. In addition, the presence of serum antibodies to type II collagen before treatment was associated with a greater likelihood of response. No significant treatment-related toxicity was noted during the study. Any patient who completed all required dosing and procedures in a previous Colloral study is eligible for enrollment in this open trial. All patients began the open study taking 20 5g each morning in orange juice (or other suitable fruit juice) approximately 20 minutes prior to breakfast. Some patients did not improve at the 20 5g daily dose and were increased incrementally up to 100 5g per day to achieve optimal clinical benefit. Most patients made follow-up visits every three months for safety and efficacy evaluations. However, some patients living long distances from Duke have been allowed to return every six months. Originally, we screened 53 patients for participation in the double- blind Oral Chicken Collagen Type II study. Four patients never started the randomized study: two had worsening arthritis during the washout phase, resulting in a change in concomitant therapy; one patient required a synovectomy of the wrist prior to treatment; another patient was unable to make the scheduled appointments. Five patients required early termination visits in the randomized trial. Three patients were withdrawn from the study because of an increase in corticosteroid therapy, which is a protocol violation. However, one of these patients continued in the open-label phase; she completed 20 of the 24 weeks of treatment when she developed acute bronchitis and was treated with a steroid taper. Another patient was terminated due to worsening arthritis. The other patient was terminated because of inefficacy and refused to return for an exit visit due to distance of travel. Her local rheumatologist treated her with parental steroids and methotrexate therapy. Forty-four patients completed the 24 week double-blind study. All patients, including one patient mentioned above who did not complete the double-blind study, elected to enter the open-label study. Twenty-five patients are currently active, two of whom transferred from other participating study sites. Twenty-one patients have withdrawn from the open trial. There are no significant adverse events related to the study medication.